The present invention relates to a novel process for the preparation of aclidinium salts. The chemical name of aclidinium is (3R)-3-[2-hydroxy(di-2-thienyl)acetoxy]-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane. The structure of the aclidinium salts is depicted below (I).
wherein:    X− is a pharmaceutically acceptable anion, such as bromide, chloride or iodide.
The preferred salt is aclidinium bromide, a quaternary ammonium salt.
Aclidinium bromide is a white to off-white crystalline powder. The active form is the R-isomer and the S-isomer has small affinity for muscarinic receptors in vitro and limited effect on acetylcholine induced bronchoconstriction. The drug is formulated as an inhalation powder, comprised of a mixture of micronized aclidinium bromide and α-lactose monohydrate.
Aclidinium bromide is a muscarinic antagonist and is available commercially as Bretaris Genuair (EU Members States), Tudorza Pressair (US and Canada) and Eklira Genuair (UK).
This compound as well as a process for its manufacture is described in WO 01/04118. Later, an improved process was described in WO2008/009397 and also presented in the article J. Med. Chem. 2θ09, 52, 5076-5092.
The process of aclidinium bromide described in WO 01/04118 has two main disadvantages:                The use of a potential genotoxic reagent—3-phenoxy propyl bromide with a large excess—5 equivalents        A long reaction time—72 hours.        
The process described in WO2008/009397 aims at overcoming these disadvantages by using specific groups of solvents, reducing the amount of 3-phenoxypropyl bromide and controlling the content of this reagent in the final product.
This process is able to reduce the reaction time to 8 hours, using a specific solvent (ketones or cyclic ethers having a boiling point between 50° C. and 210° C.) while using a reduced amount of the reagent 3-phenoxypropyl bromide. However this comes at the cost of performing the reaction under reflux.
Moreover, taking into account that the solvents considered have boiling points from 50° C. and 210° C., the reaction temperature, in some cases, must be extremely high, which brings extra operational challenges to the process.